Plasma and cellular pharmacokinetics of m-AMSA related to in vitro toxicity towards normal and leukemic clonogenic bone marrow cells (CFU-GM, CFU-L).

Plasma and cellular pharmacokinetics of m-AMSA were investigated in 5 patients with acute leukemia, using HPLC. The pharmacokinetic data served as a guideline for in vitro toxicity tests on clonogenic bone marrow cells. m-AMSA was administered as a 3-hour intravenous infusion of 100 mg/m2. Median plasma and nucleated blood cell peak concentrations were 1.25 and 6.36 micrograms/ml followed by biphasic elimination with a median T1/2 alpha alpha of 1.6 h and 0.3 h and a median T1/2 beta of 5.0 h and 5.0 h respectively. Median plasma and cellular area under the curve (AUC) for a 24-h period amounted 6.2 micrograms.h/ml and 49.8 micrograms.h/ml respectively. In vitro cellular uptake was maximal at least within 30 minutes. No differential toxicity for CFU-GM and CFU-L was observed in relation to exposure time. Median IC50 for CFU-GM and CFU-L was 2.2, 1.8 and 1.6 micrograms/ml after incubation periods of resp. 0.08, 4 and 24 h. The corresponding m-AMSA concentration x time products to achieve 50% inhibition (IAUC50) were 0.18, 7.2 and 38.4 micrograms.h/ml, respectively. 48-h prestimulation of the clonogenic bone marrow cells with Human Placenta Conditioned Medium increased sensitivity (median 1.7 x) after 4 h incubation with mAMSA. Short exposure provides maximal, concentration-related, cellular uptake, resulting in effective inhibition of growth of clonogenic bone marrow cells.